Abstract
Free-living amoeba Naegleria fowleri causes a rapidly fatal infection primary amebic meningoencephalitis (PAM) in children. The drug of choice in treating PAM is amphotericin B, but very few patients treated with amphotericin B have survived PAM. Therefore, development of efficient drugs is a critical unmet need. We identified that the FDA-approved pitavastatin, an inhibitor of HMG Co-A reductase involved in the mevalonate pathway, was equipotent to amphotericin B against N. fowleri trophozoites. The genome of N. fowleri contains a gene encoding protein farnesyltransferase (FT), the last common enzyme for products derived from the mevalonate pathway. Here, we show that a clinically advanced FT inhibitor lonafarnib is active against different strains of N. fowleri with EC50 ranging from 1.5 to 9.2 µM. A combination of lonafarnib and pitavastatin at different ratios led to 95% growth inhibition of trophozoites and the combination achieved a dose reduction of about 2- to 28-fold for lonafarnib and 5- to 30-fold for pitavastatin. No trophozoite with normal morphology was found when trophozoites were treated for 48 h with a combination of 1.7 µM each of lonafarnib and pitavastatin. Combination of lonafarnib and pitavastatin may contribute to the development of a new drug regimen for the treatment of PAM.
Highlights
Naegleria spp. are protozoa belonging to the family Vahlkampfiidae and class Heterolobosea.Like the rest of their class, they are amphizoic and they do not need to infect a host to survive
FT inhibitor lonafarnib has been extensively tested in clinical trials for malignancies [25]
It has been used in Phase I study for pediatric brain tumors [26], indicating blood–brain barrier permeability to lonafarnib
Summary
Like the rest of their class, they are amphizoic and they do not need to infect a host to survive. They can live by feeding themselves mostly on bacteria [1] and can transform into a flagellate form if the ionic concentration in the milieu changes. The amoeba can turn into a cyst stage to survive adverse conditions such as low food supply [2]. The pathology of N. fowleri is caused by the trophozoites through the release of cytolytic molecules like acid hydrolases, phospholipases, neuraminidases and phospholipolytic enzymes [4], leading to the brain tissue destruction for which N. fowleri is commonly known as brain-eating amoeba [2]
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